Modeling of Mechanisms of Selenium Bioactivity Using Density Functional Theory

Abstract

Selenium plays an important role in normal biological function through its incorporation into processes that protect against oxidative stress and promote thyroid function. The complex nature of the mechanisms involved has led to extensive study through computational modeling. However, density functional theory (DFT) modeling of the redox mechanisms of selenium is complicated by proton exchange processes catalyzed by the bulk solvent. To address this issue, we have used a method of microsolvation which we have dubbed solvent-assisted proton exchange (SAPE). These models include a few strategically placed water molecules to act as a proton shuttle and are able to obtain activation barriers that are in good agreement with experimental data and trends. Models that do not use these networks necessarily have higher barriers because they force the proton exchange through an 'unnatural' pathway that is not representative of the reaction as it occurs in solution. As a first approximation to solution-phase reactivity, SAPE models are more appropriate for drawing conclusions about the trends and energetics of these complex mechanisms. From these models, we have gained significant insight into the biological pathways of these compounds. In this chapter, we discuss our implementation of SAPE models for redox scavenging by various biorelevant organoselenium compounds, specifically arylselenols, seleninic acids and ebselen, and the related mechanism of cysteine. Finally, we discuss approaches to modeling additional important biochalcogen processes in the thyroid and in zinc finger proteins.

Effect of Methoxy Substituents on the Activation Barriers of the Glutathione Peroxidase-Like Mechanism of an Aromatic Cyclic Seleninate

“…Calculations were performed using Gaussian09 and the mPW1PW91 exchange correlation functional using the same procedures as described in previous DFT-SAPE calculations of biochalcogen systems [15,16,17,18,19,20,21]. Readers are referred to these previous studies for a more detailed discussion of the design of SAPE-type models as used in these studies.…”

“…Many organoselenium GPx mimics have complex mechanisms which are challenging to monitor experimentally. We have taken a computational approach using density functional theory (DFT) to assist in the deciphering of these mechanisms to examine bonding and mechanistic aspects of these processes [15,16]. Specifically, we have performed DFT studies of the redox mechanisms of sulfur and selenium compounds using the solvent-assisted proton exchange (SAPE) method [15,17,18,19,20,21].…”

Equilibrium between tri‐ and tetra‐coordinate chalcogenuranes is critical for cysteine protease inhibition

“…[9][10][11] Notwithstanding their most studied antioxidant activities, electrophilic selenium and tellurium species display interesting reactivities towards bionucleophiles. 12,13 Among electrophilic organochalcogen species, the hypervalent derivatives (+4 oxidation state) shows reactivities towards thiols which imply in inhibition of cysteine cathepsins, 5,14,15 arginine phosphatases 16 or tyrosine phosphatases. [17][18][19] The overexpression and exacerbate activity of cysteine cathepsins are related to several pathologies like cancer, arthritis, atherosclerosis, osteoporosis, cardiovascular and parasitic diseases.…”

Theoretical Investigation of Cyano‐Chalcogen Dimers and Their Importance in Molecular Recognition

“…Therefore, their synthesis, characterization, and uses in chemistry and molecular recognition have recently gained a lot of interest. [69][70][71][72] The application of chalcogen bonding in molecular recognition has also been employed in the selective separation of isomeric mixtures, where the receptors consist of bifurcated chalcogen bond donor centres (sulphur or selenium) towards the cyano group nitrogens of neighbouring molecules. [42,73] In addition, due to their application in crystal engineering, the structures and properties of chalcogens dicyanide in crystalline complexes [74] or in ChB with hydrogen cyanide (HCN) were recently studied.…”

“…Selenocyanate‐containing derivatives have been found to possess anticancer and chemopreventive, antifungal, and antileishmanial activity. Therefore, their synthesis, characterization, and uses in chemistry and molecular recognition have recently gained a lot of interest …”